Modulators of alpha-synuclein proteolysis and associated methods of use

Abstract

The present disclosure relates to bifunctional compounds, which find utility as modulators of α-synuclein (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon. Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

What is claimed is: 
     
         1 . A bifunctional compound having the chemical structure:
   ULM-L-PTM,   or a pharmaceutically acceptable salt thereof,   wherein:   (a) ULM is;   
       
         
           
           
               
               
           
         
         
           wherein: 
           X 1 , X 2  are each independently selected from a bond, O, NR Y3 , CR Y3 R Y4 , C═O, C═S, SO, and SO 2 ; 
           R Y3 , R Y4  are each independently selected from H, linear or branched C 1 -C 6  alkyl optionally substituted by 1 or more halo, and C 1 -C 6  alkoxyl optionally substituted by 0-3 R P  groups; 
           R P  is independently selected from H, halo, —OH, C 1 -C 3  alkyl, and C═O; 
           W 3  is selected from an optionally substituted T, an optionally substituted -T-N(R 1a R 1b )X 3 , an optionally substituted -T-N(R 1a R 1b ), an optionally substituted -T-aryl, an optionally substituted -T-heteroaryl, an optionally substituted T-biheteroaryl, an optionally substituted -T-heterocycle, an optionally substituted -T-biheterocycle, an optionally substituted —NR 1 -T-aryl, an optionally substituted —NR 1 -T-heteroaryl and an optionally substituted —NR 1 -T-Heterocycle; 
           X 3  is selected from C═O, R 1 , R 1a , and R 1b ; 
           each of R 1 , R 1a , R 1b  is independently selected from H, linear or branched C 1 -C 6  alkyl group optionally substituted by 1 or more halo or —OH groups, R Y3 C═O, R Y3 C═S, R Y3 SO, R Y3 SO 2 , N(R Y3 R Y4 ) C═O, N(R Y3 R Y4 ) C═S, N(R Y3 R Y4 ) SO, and N(R Y3 R Y4 ) SO 2 ; 
           T is selected from an optionally substituted alkyl, —(CH 2 ) n — group, wherein each one of the methylene groups is optionally substituted with one or two substituents selected from halogen, methyl, optionally substituted alkoxy, and a linear or branched C 1 -C 6  alkyl group optionally substituted by 1 or more halogen, C(O) NR 1 R 1a , or NR 1 R 1a  or R 1  and R 1a  are joined to form an optionally substituted heterocyclyl, or —OH groups or an amino acid side chain optionally substituted; and 
           n is 0, 1, 2, 3, 4, 5, or 6, 
           W 4  is 
         
       
       
         
           
           
               
               
           
         
         
            R 14a  and R 14b , are each independently selected from H, haloalkyl, and optionally substituted alkyl; 
           W 5  is an optionally substituted phenyl or an optionally substituted 5-10-membered heteroaryl, 
           R 15  is selected from H, halogen, CN, OH, NO 2 , N R 14a R 14b , OR 14a , CONR 14a R 14b , NR 14a COR 14b , SO 2 NR 14a R 14b , NR 14a  SO 2 R 14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted cyclo-heteroalkyl; and 
             is the attachment of a chemical linker moiety (L); 
         
         (b) PTM is selected from: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           wherein: 
           A, B, C, D, and E are independently selected from an optionally substituted 5- or 6-membered aryl or an optionally substituted 5- or 6-membered heteroaryl, and the optional substitutions are 1, 2, 3, or 4 substituents independently selected from H, C 1 -C 6  alkyl, O, N, halogen, C 1 -C 6  haloalkyl, C 1 -C 6  alkoxy, hydroxy, carbonyl, amino, alkylamino, dialkylamino, cyano, nitro, and —SO 2 — or an optionally substituted 4- to 7-membered cycloalkyl or heterocycloalkyl, and the optional substitutions are 1, 2, 3, or 4 substituents independently selected from H, alkyl, O, N, halogen, C 1 -C 6  haloalkyl, alkoxy, hydroxy, carbonyl, amino, alkylamino, dialkylamino, cyano, nitro, and —SO 2 —, wherein contact between circles indicates ring fusion; 
           M 1 , M 2 , and M 3  are independently selected from a single bond; O—; —S—; —NR 100 —; —SO 2 —; —S(O)—; —SO 2 NH—; —C(O)—; —C(O) NH—; and an optionally substituted C 1 -C 6  alkyl or C 1 -C 6  haloalkyl, wherein a carbon of the alkyl group may be replaced with a group independently selected from —O—, —S—, —NR 100 —, —SO 2 —, —S(O)—, —SO 2 NH—, —C(O)— or —C(O)NH—, and the optional substitutions are selected from halogen, amino, alkyl or a haloalkyl, and a two to four carbon conjugated alkenyl fragment; an alkynyl fragment; and a two to four carbon conjugated alkenyl or alkynyl fragment, wherein at least one of the carbon of the alkenyl or alkynyl group may be part of A, B, C, or D; 
           each R 100  is independently selected from H, C 1 -C 6  alkyl, and an optionally substituted C 1 -C 6  haloalkyl; 
             indicates the attachment of a chemical linker moiety (L); and 
         
         (c) L is a chemical linker moiety comprising an optionally substituted C 1 -C 50  alkyl, wherein: 
         each carbon is optionally substituted with CR L1 R L2 , O, S, SO, SO 2 , NR L3 , SO 2 NR L3 , SONR L3 , CONR L3 , NR L3 CONR L4 , NR L3 SO 2 NR L4 , CO, CR L1 ═CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , NR L3 C(═NCN)NR L4 , NR L3 C(═NCN), NR L3 C(═CNO 2 )NR L4 , C 3-11  cycloalkyl optionally substituted with 0-6 R L1  and/or R L2  groups, C 5-13  spirocycloalkyl optionally substituted with 0-9 R L1  and/or R L2  groups, C 3-11  heteocyclyl optionally substituted with 0-6 R L1  and/or R L2  groups, C 5-13  spiroheterocyclyl optionally substituted with 0-8 R L1  and/or R L2  groups, aryl optionally substituted with 0-6 R L1  and/or R L2  groups, and heteroaryl optionally substituted with 0-6 R L1  and/or R L2  groups, where R L1  or R L2 , each independently are optionally linked to other groups to form cycloalkyl and/or heterocyclyl moiety, optionally substituted with 0-4 R L5  groups; and 
         R L1 , R L2 , R L3 , R L4  and R L5  are, each independently selected from H, halo, C 1 -C 8  alkyl, O C 1 -C 8  alkyl, S C 1 -C 8  alkyl, NH C 1 -C 8  alkyl, N(C 1 -C 8  alkyl) 2 , C 3 -C 11  cycloalkyl, aryl, heteroaryl, C 3 -C 11  heterocyclyl, OC 3 -C 8  cycloalkyl, SC 3 -C 8  cycloalkyl, NHC 3 -C 8  cycloalkyl, N(C 3 -C 8  cycloalkyl) 2 , N(C 3 -C 8  cycloalkyl) (C 1 -C 8  alkyl), OH, NH 2 , SH, SO 2 C 1 -C 8 alkyl, P(O)(OC 1 -C 8  alkyl) (C 1 -C 8  alkyl), P(O)(OC 1 -C 8  alkyl) 2 , CC≡C 1 -C 8  alkyl, CCH, CH═CH(C 1 -C 8  alkyl), C(C 1 -C 8  alkyl)=CH(C 1 -C 8  alkyl), C(C 1 -C 8  alkyl)=C(C 1 -C 8  alkyl) 2 , Si(OH) 3 , Si(C 1 -C 8  alkyl) 3 , Si(OH)(C 1 -C 8  alkyl) 2 , COC 1 -C 8  alkyl, CO 2 H, halogen, CN, CF 3 , CHF 2 , CH 2 F, NO 2 , SF 5 , SO 2 NHC 1 -C 8 alkyl, SO 2 N(C 1 -C 8  alkyl) 2 , SONHC 1 -C 8  alkyl, SON(C 1 -C 8  alkyl) 2 , CONHC 1 -C 8  alkyl, CON(C 1 -C 8  alkyl) 2 , N(C 1 -C 8  alkyl)CONH(C 1 -C 8  alkyl), N(C 1 -C 8  alkyl)CON(C 1 -C 8  alkyl) 2 , NHCONH(C 1 -C 8  alkyl), NHCON(C 1 -C 8  alkyl) 2 , NHCONH 2 , N(C 1 -C 8  alkyl)SO 2 NH(C 1 -C 8  alkyl), N(C 1 -C 8 alkyl) SO 2 N(C 1 -C 8  alkyl) 2 , NHSO 2 NH(C 1 -C 8  alkyl), NHSO 2 N(C 1 -C 8  alkyl) 2 , and NHSO 2 NH 2 . 
       
     
     
         2 . The compound according to  claim 1 , wherein the ULM is: 
       
         
           
           
               
               
           
         
         wherein: 
         W 3  is selected from an optionally substituted aryl, optionally substituted heteroaryl, and 
       
       
         
           
           
               
               
           
         
         R 9  and R 10  are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, and haloalkyl; or R 9 , R 10 , and the carbon atom to which they are attached form an optionally substituted cycloalkyl; 
         R 11  is selected from an optionally substituted heterocyclic, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl, 
       
       
         
           
           
               
               
           
         
         R 12  is H or optionally substituted alkyl; 
         R 13  is selected from H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl) carbonyl, and optionally substituted aralkyl; 
         R 14a  R 14b  are each independently selected from H, haloalkyl, and optionally substituted alkyl; 
         W 5  is selected from an optionally substituted phenyl or an optionally substituted 5-10 membered heteroaryl; 
         R 15  is selected from H, halogen, CN, OH, NO 2 , N R 14a R 14b , OR 14a , CONR 14a R 14b , NR 14a COR 14b , SO 2 NR 14a R 14b , NR 14a  SO 2 R 14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted cyclo-heteroalkyl; 
         each R 16  is independently selected from H, CN, halo, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, and optionally substituted haloalkoxy; 
         o is 0, 1, 2, 3, or 4; 
         R 18  is independently selected from H, halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, and haloalkoxy; and 
         p is 0, 1, 2, 3, or 4; and 
           is the site of attachment of the chemical linker moiety (L). 
       
     
     
         3 . The compound of  claim 1 , wherein the ULM is selected from: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is selected from H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, and haloalkyl; 
         R 14a  is selected from H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, and cyclopropyl; 
         R 15  is selected from H, halogen, CN, OH, NO 2 , optionally substituted heteroaryl, optionally substituted aryl, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted cycloalkyl, and optionally substituted cycloheteroalkyl; 
         X is C, CH 2 , or C═O 
         R 3  is absent or an optionally substituted 5 or 6 membered heteroaryl; and 
         wherein   indicates the site of attachment of a chemical linker moiety (L). 
       
     
     
         4 . The compound according to  claim 1 , wherein the ULM is: 
       
         
           
           
               
               
           
         
         wherein: 
         R 14a  is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, and cyclopropyl; 
         R 9  is H; 
         R 10  is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; 
         R 11  is 
       
       
         
           
           
               
               
           
         
       
       and optionally substituted heteroaryl;
 p is 0, 1, 2, 3, or 4; 
 each R 18  is independently selected from halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, and haloalkoxy; 
 R 12  is H or C═O; 
 R 13  is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl) carbonyl, and optionally substituted aralkyl; 
 R 15  is selected from H, halogen, Cl, CN, OH, NO 2 , optionally substituted heteroaryl, an optionally substituted aryl; 
 
       
         
           
           
               
               
           
         
       
       and
 wherein   indicates the site of attachment of the chemical linker moiety (L). 
 
     
     
         5 . The compound according to  claim 1 , wherein the unit A L  of linker (L) is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein: 
         each m, n, o, p, q, r, and s are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20; and 
         N* of the heterocycloalkyl is shared with the PTM or the ULM or is linked to the PTM or the ULM via a bond. 
       
     
     
         6 . The compound according to  claim 1 , wherein the unit A L  of linker (L) is: 
       
         
           
           
               
               
           
         
         wherein: 
         each m, n, o, p, q, r, and s are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20; and 
         N* of the heterocycloalkyl is shared with the PTM or the ULM or is linked to the PTM or the ULM via a bond. 
       
     
     
         7 . The compound according to  claim 1 , wherein the unit A L  of linker (L) is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein N* of the hetero-cycloalkyl is shared with the PTM or the ULM or is linked to the PTM or the ULM via a bond. 
       
     
     
         8 . The compound of  claim 1 , wherein the linker (L) is: 
       
         
           
           
               
               
           
         
         wherein: 
         W L1  and W L2  are each independently absent, a 4-8 membered ring with 0-4 heteroatoms, optionally substituted with RQ, each RQ is independently a H, halo, OH, CN, CF 3 , optionally substituted linear or branched C 1 -C 6  alkyl, optionally substituted linear or branched C 1 -C 6  alkoxy, or 2 RQ groups taken together with the atom they are attached to, form a 4-8 membered ring system containing 0-4 heteroatoms; 
         Y L1  is each independently a bond, optionally substituted linear or branched C 1 -C 6  alkyl and optionally one or more C atoms are replaced with O; or optionally substituted linear or branched C 1 -C 6  alkoxy; 
         n is 0, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and 
            indicates the attachment point to the PTM or ULM moieties. 
       
     
     
         9 . The compound according to  claim 1 , wherein the linker (L) is: 
       
         
           
           
               
               
           
         
         wherein: 
         W L1  and W L2  are each independently selected from absent, aryl, heteroaryl, cyclic, heterocyclic, C 1 -C 6  alkyl and optionally one or more C atoms are replaced with O, C 1 -C 6  alkene and optionally one or more C atoms are replaced with O, C 1 -C 6  alkyne and optionally one or more C atoms are replaced with O, bicyclic, bi-aryl, bi-heteroaryl, or bi-heterocyclic, each optionally substituted with R Q , each R Q  is independently a H, halo, OH, CN, CF 3 , hydroxyl, nitro, C≡CH, C 2-6 alkenyl, C 2-6 alkynyl, optionally substituted linear or branched C 1 -C 6  alkyl, C 1 -C 6  alkoxy (linear, branched, optionally substituted), optionally substituted linear or branched OC 1-3 alkyl, OH, NH 2 , NR Y1 R Y2 , CN, or 2 R Q  groups taken together with the atom they are attached to, form a 4-8 membered ring system containing 0-4 heteroatoms; 
         Y L1  is each independently selected from a bond, NR YL1 , O, S, NR YL2 , CR YL1 R YL2 , C═O, C═S, SO, SO 2 , optionally substituted linear or branched C 1 -C 6  alkyl and optionally one or more C atoms are replaced with O; and optionally substituted linear or branched C 1 -C 6  alkoxy; 
         Q L  is selected from a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, optionally bridged, optionally substituted with 0-6 R Q , each R Q  is independently H, optionally substituted linear or branched C 1 -C 6  alkyl, or 2 R Q  groups taken together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms; 
         R YL1  and R YL2  are each independently selected from H, OH, and optionally substituted linear or branched C 1 -C 6  alkyl, or R 1 , R 2  together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms; 
         n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and 
            indicates the attachment point to the PTM or the ULM moieties. 
       
     
     
         10 . A compound selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         11 . A pharmaceutical composition comprising a compound of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         12 . The pharmaceutical composition of  claim 11 , wherein the composition further comprises at least one additional bioactive agent. 
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein the additional bioactive agent is anti-neurodegenerative agent. 
     
     
         14 . A method of treating a disease or disorder, comprising administering an effective amount of a compound of  claim 1  to a subject;
 wherein the disease or disorder is associated with α-synuclein accumulation and aggregation. 
 
     
     
         15 . The method of  claim 14 , wherein the disease or disorder is a α-synucleinopathies or a neurodegenerative disease associated with α-synuclein accumulation and aggregation. 
     
     
         16 . The method of  claim 14 , wherein the disease or disorder is Parkinson Disease, Alzheimer's Disease, dementia, dementia with Lewy bodies, or multiple system atrophy. 
     
     
         17 . The method of  claim 14 , wherein the disease or disorder is Parkinson's Disease. 
     
     
         18 . A pharmaceutical composition comprising the compound of  claim 10 , and a pharmaceutically acceptable carrier.